To determine if there were differences in inducibility between hepatic and intestinal microsomal xenobiotic-metabolizing enzymes. Phenobarbital (PB) or 3-methylcholanthrene (3-MC) was given orally (po) or intraperitoneally (ip) to mouse, rat, guinea pig, and rabbit. Differences in the inducibility of xenobiotic-metabolizing enzymes due to route of administration if PB were observed in guinea pig, mouse, and rat small intestine but not in liver. Differential effects of po- and ip-administered 3-MC on hepatic aryl hydrocarbon hydroxylase (AHH) and cytochrome P-450 were noted in rat and guinea pig. The induction of intestinal xenobiotic-metabolizing enzymes varied with the animal species and the substrate used. None of the rabbit intestinal xenobiotic-metabolizing enzymes was induced by PB or 3-MC treatment --even in rabbits fed semi-purified diet. However, rabbit intestinal xenobiotic metabolizing enzymes were not totally resistant to environmental insult since starvation significantly reduced activities. Vitamin A deficiency or excess feed elicited quantitative and qualitative differences between the species and tissues in their ability to activate or inactivate foreign chemicals.